Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Addition of soluble molecules obtained from sonicated Mycobacterium leprae markedly suppressed the proliferative response to the mitogen anti-CD3 of peripheral blood mononuclear cells and isolated T cells. Suppression was nonspecific and occurred with cells from lepromatous and tuberculoid leprosy patients as well as control donors. The purified lipoarabinomannans from M. leprae and Mycobacterium tuberculosis had a similar spectrum of inhibition whereas their deacylated derivatives were without effect. All mycobacterial preparations of either a crude or purified state, which suppressed cellular responses, contained appreciable quantities of bacterial lipopolysaccharide by the Limulus amebocyte assay. Contamination with lipopolysaccharide could account for the extent and nonselectivity of the T-cell suppression. Suppression was also monocyte-dependent and in part due to the release of arachidonate metabolites of the cyclooxygenase pathway.
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PMID:Suppression of T-cell proliferation by Mycobacterium leprae and its products: the role of lipopolysaccharide. 168 64

The metabolism of bioreactive lipid mediators was studied in two types of activated macrophages (M phi). We compared the capacity of resident and activated M phi to release, upon a zymosan challenge, cyclooxygenase and lipoxygenase products as well as PAF-acether (platelet-activating factor) and its 2-lyso precursor. Activated M phi were obtained from mice injected intraperitoneally either with nonviable C74 streptococci (St-M phi) or with trehalose dimycolate, a defined immunostimulant isolated from Mycobacterium tuberculosis (TDM-M phi). Both activated populations exhibited common features: conversion of endogenous [14C]arachidonic acid into prostaglandin E2 and thromboxane A2 rather than into prostaglandin I2 and low biosynthesis of PAF-acether, probably due to an impairment of the acetylation step. However, contrary to St-M phi, TDM-M phi did not display a marked overall reduction of arachidonate metabolism. In addition, as compared to resident M phi, TDM-M phi presented a ratio of thromboxane B2/6-ketoprostaglandin F1 alpha 30-fold higher, a better conversion of leukotriene C to leukotriene D and a higher capacity to release the PAF-acether they synthesize. These macrophages thus seem to be valuable tools for studying the formation of mediators and for determining specific markers of an activated state.
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PMID:Lipid-mediator synthesis in peritoneal macrophages from mice injected with immunostimulants. 613 93

There is evidence indicating that bioreactive lipid mediators, PAF-acether (platelet-activating factor: 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) and arachidonic acid (AA) metabolites, are formed upon deacylation of ether lipids. M phi obtained from mice treated with the sterile irritant thioglycolate exhibited an impaired formation of PAF-acether, leucotrienes (LT) C4 and prostaglandins (PG). In order to assess whether the impaired formation in lipid mediators is a general feature of M phi found at inflammatory sites, we have compared the capacity of resident (R-M phi) and immunostimulant-activated M phi to release, upon a zymosan challenge, PAF-acether and cyclooxygenase and lipoxygenase products. Activated M phi was obtained from mice injected intraperitoneally with non-viable C74 streptococci (St-M phi), bacilli Calmette-Guerin (BCG-M phi) or trehalose dimycolate (TDM-M phi), a defined immunostimulant isolated from Mycobacterium tuberculosis. All populations were capable of releasing PAF-acether. However, the amount of cell-associated PAF-acether was reduced by 75-90% in activated M phi populations as compared to R-M phi. Although the acetyltransferase level was comparable, acetyl-CoA supplementation restored the formation of PAF-acether by activated M phi to control (R-M phi) level. The amount of 14C-AA metabolites released by St-M phi was much lower compared with TDM-M phi or R-M phi, as was the amount of LTC4 detected as SRS contractile activity after HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of immunomodulators in the production of lipid mediators by macrophages (M phi). 659 98

We have previously reported that impaired in vitro cellular immunity is a common finding in patients with nontuberculous mycobacterioses and that the subnormal responses may be improved by indomethacin. Subsequently, we have studied the in vivo effects of indomethacin on cell-mediated immune functions of four patients with Mycobacterium avium-intracellulare infections. Prior to treatment none of the patients had delayed cutaneous reactions to purified protein derivative (PPD) of the tubercle bacillus, and their lymphocytes had subnormal in vitro proliferation responses to tuberculins from M. tuberculosis and M. avium-intracellulare and to phytohemagglutinin. The administration of indomethacin reconstituted both the in vitro lymphocyte responses and delayed cutaneous hypersensitivity. We propose that the impairment of T-cell dependent immune functions is mediated by a suppressive factor (or factors) that is a metabolic product(s) of the cyclooxygenase pathway of arachidonic acid metabolism. Preferential inhibition of this pathway with indomethacin allows the expression of cell-mediated responses.
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PMID:Modulation of immunologic responses in nontuberculous mycobacterial infections with indomethacin. 672 31

Human macrophages (M phi) from most donors respond to inoculation with Mycobacterium avium serovar 4 (M. avium) by tumor necrosis factor alpha (TNF-alpha) production, which is of critical importance for proper defense against microorganisms. An initial infection of M phi with M. avium results in an incapacity to accumulate TNF-alpha mRNA after reinfection with M. avium, indicating adaptation to a hyporesponsive state by preexposure of the cells to M. avium. Adaptation to stimulation with M. avium is abrogated by the cyclooxygenase inhibitor indomethacin. In the presence of prostaglandin E2, indomethacin-exposed, M. avium-treated M phi remain unresponsive to a subsequent M. avium stimulus to increase steady-state TNF-alpha mRNA, suggesting that prostaglandin E2 is instrumental for the adaptation to an M. avium challenge. TNF-alpha mRNA accumulation induced by a second M. avium stimulus in the presence of indomethacin is blocked by the protein tyrosine kinase inhibitor herbimycin. In contrast, the initial M phi response to M. avium is inhibited by staurosporin, an inhibitor of phospholipid Ca(2+)-dependent protein kinases, indicating that the initial and the successive TNF-alpha responses to M. avium are dependent on different mechanisms.
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PMID:Human macrophages acquire a hyporesponsive state of tumor necrosis factor alpha production in response to successive Mycobacterium avium serovar 4 stimulation. 772 3

CI-986 is a potent inhibitor of 5-lipoxygenase and cyclooxygenase pathway product biosynthesis from rat basophilic leukemia (RBL) cells. Because metabolites from these pathways have proinflammatory properties, CI-986 was evaluated in several acute and chronic models of inflammation and hyperalgesia. The compound inhibited swelling in the carrageenan footpad edema, Mycobacterium foot-pad edema and adjuvant arthritis models of inflammation with ID40 values of 1.0, 7.7., and 7.2 mg/kg, respectively. It was roughly equivalent in potency to the standard selective cyclooxygenase inhibitor, naproxen (ID40 = 0.7, 6.3, and 3.8 mg/kg, respectively). CI-986 was also evaluated in the acetic acid induced writhing hyperalgesia assay (ID50 = 0.23 mg/kg) and was approximately equipotent with indomethacin (ID50 = 0.87 mg/kg). Although the effects of CI-986 were similar to those of standard nonsteroidal antiinflammatory drugs (NSAIDs) in the inflammation models, its gastrointestinal profile was unique. CI-986 caused no gastrointestinal irritation at doses up to 200 mg/kg in acute and chronic studies. In contrast, standard NSAIDs caused ulcers at doses of 3.7-37 mg/kg after a single dose. Moreover, CI-986 inhibited the release of LTC4 and PGE2 by gastric mucosa and reduced mucosal and vascular damage induced by oral administration of absolute ethanol to rats. These results indicate that CI-986 is a potent nonulcerogenic antiinflammatory agent with novel pharmacologic properties.
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PMID:The pharmacologic effects of 5-[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, choline salt (CI-986), a novel inhibitor of arachidonic acid metabolism in models of inflammation, analgesia and gastric irritation. 814 Feb 59

Lipoarabinomannan (LAM) is the major arabinose- and mannose-containing phosphorylated lipopolysaccharide (LPS) in mycobacterial cell walls. LAM preparations from a virulent strain (Erdman) (LAM(Erdman)) and an attenuated strain (H37Ra) (LAMH37Ra) of Mycobacterium tuberculosis, as well as from M. leprae (a virulent mycobacterium), were analyzed for their effects on various macrophage (M phi) effector functions. LAMH37Ra, like gram-negative LPS, exhibited a dose-dependent ability to induce tumor necrosis factor alpha (TNF-alpha) production in normal M phi, and gamma interferon (IFN-gamma) priming of the M phi greatly augmented the levels of TNF-alpha. However, the effects of LAMH37Ra were unaffected by polymyxin B, which totally abrogated the effects of LPS. LAM(Erdman) and LAM from M. leprae, on the other hand, induced virtually no TNF-alpha production. Analysis of M phi mRNA by reverse transcription-polymerase chain reaction revealed that the levels of production. Analysis of M phi mRNA by reverse transcription-polymerase chain reaction revealed that the levels of TNF-alpha mRNA induced by the various preparations correlated with the levels of TNF-alpha protein detected. Interestingly, both LAMH37Ra and LAM(Erdman) could block subsequent IFN-gamma- and LPS-induced M phi activation, a previously reported measure of the potent ability of LAM to down-regulate M phi effector functions. Two lines of evidence suggested, however, that M phi cyclooxygenase products did not play a role in this down-regulation. LAMH37Ra and LPS could induce the production of NO2- in both normal and IFN-gamma-primed M phi, whereas LAM(Erdman) could stimulate NO2- production only in primed M phi. Both LAMH37Ra and LAM(Erdman) could substitute for LPS as a triggering signal for IFN-gamma-primed M phi in a toxoplasma killing assay. The triggering ability of LAM(Erdman), however, was abrogated by an anti-TNF-alpha antibody, suggesting that sufficient TNF-alpha production was stimulated by LAM(Erdman) to drive a M phi function relevant in host resistance. Thus, mycobacterial LAM is a potent regulator of M phi functions, a fact that may have important consequences in mycobacterial disease.
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PMID:Regulation of murine macrophage effector functions by lipoarabinomannan from mycobacterial strains with different degrees of virulence. 840 6

We evaluated the in vivo therapeutic activities of benzoxazinorifamycin KRM-1648, clarithromycin (CAM) and levofloxacin (LVFX) against Mycobacterium avium infection induced in mice. Mice infected intravenously with M. avium (1.4 x 10(7)) were given KRM-1648 (20 mg/kg), CAM (10 mg/kg), or LVFX (5 mg/kg) alone, or combination of KRM-1648 with diclofenac sodium (1.25 mg/kg) by gavage, once daily, five times per week, from day 1 for up to 8 weeks. The bacterial loads in the lungs and spleens were determined by counting colony forming units of the organisms in the tissue homogenates of the visceral organs using 7H11 agar plates. Both KRM-1648 and CAM caused significant levels of bacteriological response in mice treated with these drugs, while LVFX exerted no appreciable therapeutic effect. The therapeutic efficacies of test antimicrobials were in the order, KRM-1648 > CAM > > LVFX. The combined use of diclofenac sodium with KRM-1648 did not affect the expression of therapeutic activity of KRM-1648. This excludes the possibility that cyclooxygenase-dependent inflammatory reactions may be involved in the establishment of persistent bacterial growth of M. avium organisms at the sites of infection in mice. Furthermore, the present study showed that the parameters of in vitro antimicrobial activities of drugs such as MIC and MBC values are not useful in predicting their therapeutic outcome in M. avium-infected mice.
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PMID:[In vivo activities of benzoxazinorifamycin KRM-1648, clarithromycin, and levofloxacin, or combination of KRM-1648 with diclofenac sodium against Mycobacterium avium infection induced in mice]. 929 12

Adjuvant arthritis, induced by Mycobacterium butyricum, is an experimental immunopathy that shares many features of human rheumatoid arthritis and, as such, is one of the most widely used models for studying the anti-inflammatory activity of compounds. In rats with adjuvant induced arthritis, IgG antibodies to M. butyricum have been detected and autoantigens that cross react with mycobacteria may be involved in the pathogenesis of adjuvant arthritis. In this study, the anti-inflammatory and immunosuppressive activities of two cyclooxygenase-2 selective inhibitors, flosulide and L-745,337, at doses of 0.1, 1 and 5 mg/kg/day, were examined in adjuvant arthritic rats. After 14 days of treatment, a clear dose-dependent inhibition of plantar edema was seen for both flosulide (ID50 lower than 0.1 mg/kg) and L-745,337 (ID50 = 0.4 mg/kg). Plasma levels of IgG anti-M. butyricum antibodies were also decreased by both drugs. In each case the maximal immunosuppressive effect was observed at doses lower than 5 mg/kg. The non-selective COX-2 inhibitor, indomethacin (1 mg/kg) decreased paw edema by 65% and the levels of IgG anti-M. butyricum by 45%. Neither cyclooxygenase selective inhibitors nor indomethacin decreased the delayed hypersensitivity reaction induced by M. butyricum. Thus, in vivo inhibition of COX-2 inhibited articular swelling and also the humoral immune response to Mycobacterium.
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PMID:Selective cyclooxygenase-2 (COX-2) inhibitors reduce anti-Mycobacterium antibodies in adjuvant arthritic rats. 1066 81

The effects of cyclooxygenase (COX)-2 antisense oligodeoxynucleotide (ODN) in induction of adjuvant-induced arthritis were investigated. Female Lewis rats were injected with Mycobacterium butyricum intradermally at the base of tails to induce arthritis. Synthetic 18 mer phosphorothioate ODNs corresponding to the translation initiation site of rat COX-2 mRNA were prepared. The antisense (AS), sense (S), and "scrambled" (Sc) ODNs were intraperitoneally administered. Arthropathy was evaluated with arthritis score, paw edema, and histological examination. Expression of COX-1 and -2 protein and mRNA were examined with immunostaining and reverse-transcription polymerase chain reaction, respectively. COX-2 AS ODN significantly suppressed induction of arthritis in a dose-dependent manner without severe adverse effects, whereas S and Sc ODNs did not show significant inhibitory effects. COX-2 mRNA and protein expression were also suppressed only by COX-2 AS ODN without any alteration of COX-1 expression. These data suggest that selective inhibition of COX-2 with AS ODN may have a therapeutic potency in the treatment of rheumatoid arthritis.
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PMID:Selective inhibition of cyclooxygenase-2 with antisense oligodeoxynucleotide restricts induction of rat adjuvant-induced arthritis. 1070 68


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